Acetylcholine, a major neurotransmitter in mammalian organisms, is released from central, sympathetic and peripheral neurons. Acetylcholine is involved in a wide range of biological functions including motor, sensory, learning and memory, sexual activity, sleep, and autonomic control of cardiovascular, respiratory, gastrointestinal and urogenital functions. Modulation of cholinergic function has been found to have beneficial effects in a number of pathologies such as Alzheimer's disease, Parkinson's disease and olivopontocerebellar atrophy.
Actions of the neurotransmitter acetylcholine are modulated by two classes of receptors, muscarinic and nicotinic, on the basis of the effects of the prototypical cholinergic agonists, muscarine and nicotine. Nicotine administration increases dopamine efflux in the striatum, nucleus accumbens and cortex. Nicotine administration also causes norepinephrine release in cortex and hippocampus and glutamate release in the cortex. The effects of nicotine on glutamate have also been demonstrated in behavioral tests where NMDA antagonist MK-801 eliminated the memory improvement caused by nicotine. Nicotine also stimulates acetylcholine release and thus exerts some of its actions via muscarinic receptors.
Nicotine affects cardiovascular function by sympathetic neural stimulation. The endocrine-mediating effects of nicotine release include a release of beta-endorphins, and stimulation of ACTH and cortisol release. Nicotine also induces lipolysis and subsequent release of free fatty acids into the circulation.
Behavioral experimentation in rodents, monkeys and humans has shown that nicotine agonists can improve performance in cognitive tasks while nicotine antagonists impair performance of those tasks. The cognition-enhancing effects of nicotine have beneficial effects on attention deficit patients.
Epidemiological studies suggest that smokers have approximately a two-fold lower risk of being diagnosed with Parkinson's disease than non-smokers and nicotine may be partly responsible for this apparent protective affect. A similar disparity is observed between smokers and non-smokers for neuroleptic induced Parkinsonism.
Mammalian nicotine receptors belong to a class of pentameric ligand gated ion channels. In a rat brain, at least eight α(α2-α9) and three 62 (β2-β4) subunits have been cloned. In the mammalian brain, the most abundant subtype is α4β2.
In recent years, a realization that nicotinic acetylcholine receptor mediated biochemical activities can exert beneficial effects on human neurological disorders has fueled interest in the development of compounds that have better safety and pharmacokinetic profiles than nicotine. These efforts have resulted in the development of the compounds ABT418, ABT089, ABT-594, GTS-21 and SIB-1765f and RJR-2403, which are illustrated in FIG. 1.
Anabaseine and its derivative GTS-21 are known to interact with both α4β2 and α7 nicotinic acetylcholine receptor subtypes. In functional assays, GTS-21 appears to act as a potent partial agonist in α7 receptors. On the other hand, it is a weak partial agonist at α4β2 receptors.
The nicotine analog SIB-1765f displays comparable binding affinity with nicotine in rat cortical membranes. Electrophysiological recordings of current responses in Xenopus oocytes expressing recombinant human nicotinic acetylcholine receptors revealed that SIB-1508y produced currents that ranged between 20 and 50% of the response elicited by an equimolar concentration of acetylcholine in oocytes expressing the α2β2, α2β4, α3β2, α4β2 and α4β4 nicotinic acetylcholine receptor subtypes. No detectable response was obtained from cells expressing the α7 human subtype and only a minimal response was obtained from cells expressing the α3β4 subtype. In contrast, nicotine is a potent agonist for both α7 and α3β4 nicotinic acetylcholine receptor subtypes.
RJR-2403 displaces [3H]-nicotine binding in rat cortex with moderately high potency (Ki=26±3 nM) reflecting high affinity for the α4β2 nicotinic acetylcholine receptor subtype. In contrast, the compound is significantly less potent at the α7 subtype (Ki=36 micromolar). RJR-2403 is also comparable to nicotine in evoking 86Rb+ efflux from rat thalamic synaptosomes, but only one tenth as active as nicotine in stimulating [3H]-dopamine release from striatal synaptosomes. At concentrations of up to 1 mM, RJR-2403 does not significantly activate nicotinic acetylcholine receptor as PC12 cells or human muscle nicotinic acetylcholine receptor subtype. The low potency of RJR-2403 at these peripheral nicotinic acetylcholine receptors led investigators to conclude that in contrast to nicotine this compound is selective for CNS nicotinic acetylcholine receptors.
ABT-418 is a potent nicotine ligand which interacts stereoselectively with a neuronal [3H]-cytisine binding site (Ki=4.5 nanomolar). ABT-418 also activates human a nicotinic acetylcholine receptors expressed in Xenopus oocytes and stimulates dopamine release from striatal slices. However, the potency of this compound is lower than that of (−)-nicotine. Because the α3 subunit has been linked to dopamine release, the lower potency of ABT418 in the latter assay is viewed as an indication that this compound displays lower affinity for the α3 subunit than (−)-nicotine.
ABT-089 and ABT-594 are members of the 3-pyridyl alkyl ether class of nicotinic acetylcholine receptor ligands. Structurally, both compounds differ from nicotine and ABT-418 in that the pyridyl and cycloalkylamine fragments are separated by an oxymethylene bridge. The presence of this bridge results in increased flexibility relative to nicotine and increased separation between the centroid of the pyridyl moiety and the amino group of the cycloalkylamine.
ABT-594 is a potent inhibitor of [3H]-nicotine binding to the neuronal α4β2 nicotinic acetylcholine receptor subtype in rat brain (Ki=37 picomolar) and in cells expressing the human receptor (Ki=55 picomolar). Compared to ABT-594, ABT-089 is about 300-fold less potent as an inhibitor of [3H]-nicotine binding to the α4β2 nicotinic-acetylcholine subtype. However, the affinity of this analog for the α7 neuronal subtype and ganglionic nicotinic acetylcholine receptors is comparable to that of ABT-594.
Currently, there is a need for novel and effective treatments for disorders such as Alzheimer's disease, Parkinson's disease, schizophrenia, depression, attention deficit/hyperactivity disorder, neuropathic pain, ulcerative colitis, urinary incontinence, and olivopontocerebellar atrophy. While nicotine has been shown to exhibit beneficial effects in treating such disorders, its' use has been associated with detrimental side effects on cardiovascular and gastrointestinal function. Consequently, there is a need for novel nicotinic agonists or antagonists that can effectively treat these disorders without eliciting the detrimental side effects of nicotine. There is also a need for pharmacological tools for the further study of the physiological processes associated with disfunctional acetylcholine production.